Intrinsic cardiac enkephalins inhibit vagal bradycardia in the dog

Caffrey, James L.; Mateo, Zaira; Napier, Leslie; Gaugl, J. F.; Barron, Barbara A.

doi:10.1152/ajpheart.1995.268.2.h848

Cited by 25 publications

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“…The case for the ␦ 1 -receptor is less clear because the pre-or postjunctional character of the response has not been addressed. However, no improved vagal function was noted when MEAP and methacholine were combined (8). The data thus far are, however, consistent with the hypothesis suggested by Crain and Shen (10) to explain the bimodal effects of opioids on the action potential duration in cultured dorsal root ganglion cells.…”

Section: Discussionsupporting

confidence: 89%

“…The vagolytic response was presumed to be mediated through the prejunctional inhibition of acetylcholine release. This assumption was based on the failure of MEAP to alter the bradycardia following the addition of the direct-acting cholinergic methacholine (8). Although the ␦ 2 -receptor is probably located on the vagal nerve terminals, MEAP may act indirectly on an intermediate cell or interneuron.…”

Section: Discussionmentioning

confidence: 99%

“…The systemic infusion of MEAP interrupted the vagal control of heart rate, coronary blood flow, and contractile activity (6,8). Opiate receptor participation was confirmed when each effect was prevented by pretreatment with the high-affinity nonselective opiate antagonist diprenorphine.…”

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confidence: 94%

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Bimodal δ-opioid receptors regulate vagal bradycardia in canine sinoatrial node

Jackson

Yoshishige

Caffrey

2003

American Journal of Physiology-Heart and Circulatory Physiology

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frey. Bimodal ␦-opioid receptors regulate vagal bradycardia in canine sinoatrial node. Am J Physiol Heart Circ Physiol 285: H1332-H1339, 2003 10.1152/ajpheart.00353.2003 introduced into the interstitium of the canine sinoatrial (SA) node by microdialysis interrupts vagal bradycardia. In contrast, raising endogenous MEAP by occluding the SA node artery improves vagal bradycardia. Both are blocked by the same ␦-selective antagonist, naltrindole. We tested the hypothesis that vagal responses to intranodal enkephalin are bimodal and that the polarity of the response is both doseand opioid receptor subtype dependent. Ultralow doses of MEAP were introduced into the canine SA node by microdialysis. Heart rate frequency responses were constructed by stimulating the right vagus nerve at 1, 2, and 3 Hz. Ultralow MEAP infusions produced a 50-100% increase in bradycardia during vagal stimulation. Maximal improvement was observed at a dose rate of 500 fmol/min with an ED 50 near 50 fmol/min. Vagal improvement was returned to control when MEAP was combined with the ␦-antagonist naltrindole. The dose of naltrindole (500 fmol/min) was previously determined as ineffective vs. the vagolytic effect of higher dose MEAP. When MEAP was later reintroduced in the same animals at nanomoles per minute, a clear vagolytic response was observed. The ␦ 1-selective antagonist 7-benzylidenenaltrexone (BNTX) reversed the vagal improvement with an ED 50 near 1 ϫ 10 Ϫ21 mol/min, whereas the ␦2-antagonist naltriben had no effect through 10 Ϫ9 mol/min. Finally, the improved vagal bradycardia previously associated with nodal artery occlusion and endogenous MEAP was blocked by the selective ␦ 1-antagonist BNTX. These data support the hypothesis that opioid effects within the SA node are bimodal in character, that low doses are vagotonic, acting on ␦ 1-receptors, and that higher doses are vagolytic, acting on ␦ 2-receptors. heart rate; enkephalins; opiate receptors; microdialysis; parasympathetic nervous system THE NORMAL CARDIAC RHYTHM arises in the sinoatrial (SA) node. The resulting heart rate is largely determined by the intrinsic activity of the resident pacemaker cells and the tonic restraint applied to them by the efferent postganglionic vagal nerves that innervate the node. The intrinsic rate of the pacemaker cells is significantly higher than the resting heart rate, and rapid increases in heart rate are generally accomplished by reducing vagal nerve traffic. Concentrated cholinesterase activity within the SA node provides for nearly instantaneous hydrolysis of interstitial neurotransmitter and a rapid increase in heart rate as the rate of transmitter release is reduced. An effective heartbeat is highly dependent on the coordinated distribution of electrical signals from the SA node and on the subsequent electromechanical coupling of conducting and contractile elements. Disturbances in this delicate electromechanical network lead to serious arrhythmias, and an active healthy vagal function appears to exert a trophic influence over the rhythmic...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Bimodal δ-opioid receptors regulate vagal bradycardia in canine sinoatrial node

Jackson

Yoshishige

Caffrey

2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…The relative significance of individual endogenous enkephalins is also unclear. Although all the endogenous enkephalins are qualitatively ␦-agonists, MEAP may be more potent in some respects, perhaps in part because of a slower rate of degradation (6,7,19). Despite potential differences, however, all three enkephalins evaluated in the present study were cardioprotective when added exogenously.…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning increases the bioavailability of cardiac enkephalins

Younès¹,

Pepe²,

Yoshishige³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Growing evidence suggests that cardiac enkephalins and their receptors are involved in ischemic preconditioning (IPC). Because there is no evidence for vesicular storage of small bioactive enkephalins in the heart, studies were designed to test the hypothesis that ischemia depletes cardiac enkephalins and that IPC preserves the same enkephalins by accelerating their processing from the larger proenkephalin precursor (PEP) pool. The precursors and two bioactive representatives, Met-enkephalin (ME) and Met-enkephalin-Arg-Phe (MEAP), were separated by size-exclusion chromatography and quantified by radioimmunoassay. Isolated perfused rat hearts were prepared and exposed to global ischemia. After 30 min of global ischemia and 40 min of reflow, the PEP pool was reduced (from 17.99 Ϯ 1.52 to 14.20 Ϯ 2.38 pmol/g wet wt), MEAP increased by 53%, and ME declined by 68%. The sum of the two smaller peptides was unchanged (9.78 Ϯ 0.83 vs. 9.33 Ϯ 2.81). Thus the total enkephalin peptide content was not altered (27.77 Ϯ 1.69 vs. 24.10 Ϯ 4.75). Peptide distribution after ischemia and reflow was also unaltered by pretreatment with peptidase inhibitors. However, when the hearts were preconditioned, the PEP pool remained significantly lower and both of the bioactive peptides, MEAP and ME, were elevated (ϩ49% and ϩ86%, respectively). The decline in the PEP pool was prevented by peptidase inhibition and the rise in MEAP was exaggerated. In separate protocols, synthetic enkephalins (ME, MEAP, and Leuenkephalin) were added to the coronary inflow before 30 min of global ischemia and throughout the subsequent reflow. The added enkephalins (10 Ϫ8 M) had no inotropic effect on baseline function but completely prevented the mechanical dysfunction observed in untreated controls during reflow. Thus IPC appears to increase available bioactive enkephalins (MEAP ϩ ME) within the heart by enhancing synthesis of precursors and their subsequent processing from the PEP pool. opioid peptides; heart; opioid peptide processing THE ENDOGENOUS CARDIAC OPIOIDS and their receptors are considered to be potent modulators of cardiovascular function, inasmuch as they have been implicated in stem cell cardiogenesis (30, 32), cardiac development (27), cardiac aging (3), cardiomyopathy (31, 33), hypertension (38), and hibernation (2). Myocardial infarction increased the abundance of opioid peptide mRNA and the expression of the associated opioid peptides (22). Opioids and their receptors have been demonstrated to protect against myocardial ischemia (8,18,21,26). Opioid receptor blockade prevents the cardioprotective effect of ischemic preconditioning (IPC) (for review see Ref. 14). The cardioprotective effects of opioids are associated with opening of ATP-sensitive K ϩ channels and inhibition of glycogen synthase-␤. Thus opiate receptor signaling is an important facet of the myocardial adaptation to stress, although the source of the opioids and the location of their receptors are less well defined.The concentration of circulating opioid peptides (9) is presumed...

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“…In the canine heart, MEAP interrupted vagal transmission within the sinoatrial (SA) node at a site proximal to the muscarinic receptors resident on the pacemaker cells (5,14). Extensive agonist/antagonist profiles indicated that the receptors responsible for these observations are ␦ 2 -opioid receptors (15,20).…”

mentioning

confidence: 99%

Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

Farias

Jackson

Johnson

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node. Am J Physiol Heart Circ Physiol 285: H2001-H2012, 2003. First published July 24, 2003 10.1152/ ajpheart.00275.2003.-Endogenous opioids and nitric oxide (NO) are recognized modulators of cardiac function. Enkephalins and inhibitors of NO synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that NO systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cGMP pathway. Microdialysis probes were inserted into the SA node, and they were perfused with nonselective (N -nitro-L-arginine methyl ester) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate L-arginine. Introduction of MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of L-arginine and not by D-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor S-nitroso-N-acetyl-penicillamine, the protein kinase G activator 8-bromo-cGMP, or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals. phosphodiesterase; nitric oxide; opioids; cAMP; heart rate; cardiac pacemaker ENDOGENOUS ENKEPHALINS and nitric oxide (NO) are gaining recognition for their effects on cardiac parasympathetic function (4-11, 13-15, 17-21). The endogenous opioid methionine-enkephalin-arginine-phenylalanine

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Intrinsic cardiac enkephalins inhibit vagal bradycardia in the dog

Cited by 25 publications

References 0 publications

Bimodal δ-opioid receptors regulate vagal bradycardia in canine sinoatrial node

Bimodal δ-opioid receptors regulate vagal bradycardia in canine sinoatrial node

Ischemic preconditioning increases the bioavailability of cardiac enkephalins

Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

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